Atlas of Genetics and Cytogenetics in Oncology and Haematology

Taking over the Atlas
Dear Colleagues,
The Atlas, once more, is in great danger, and I will have to proceed to a collective economic lay-off
of all the team involved in the Atlas before the begining of April 2015 (a foundation having suddenly
withdrawn its commitment to support the Atlas).
I ask you herein if any Scientific Society (a Society of Cytogenetics, of Clinical Genetics, of Hematology,
or a Cancer Society, or any other...), any University and/or Hospital, any Charity, or any database would be
interested in taking over the Atlas, in whole or in part. If taking charge of the whole lot is too big, a
consortium of various actors could be the solution (I am myself trying to find partners).
Could you please spread the information, contact the relevant authorities, and find partners.
Survival of the Atlas will be critically dependant upon your ability to find solutions (and urgently!).
Kind regards.
Jean-Loup Huret jlhuret@AtlasGeneticsOncology.orgDonations are also welcome
If each casual visitor gives 3 Euros or Dollars, the Atlas is saved in a week !
If each professional gives 100 Euros or Dollars once a year (now), the Atlas is saved in 2 weeks !
Don't let the Atlas imminent demise
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NTRK3 (neurotrophic tyrosine kinase, receptor, type 3)

Starts at 88520596 and ends at 88799962 bp from pter ( according to hg19-Feb_2009) [Mapping]

DNA/RNA

Description

The gene for NTRK3 is located on chromosome 15 q25 and is encoded by 20 exons. Exon 1 codes for the translation initiation codon (ATG) and the signal sequence (SS), while the stop codon is located in exon 18. Exons 1 to 4 encode the Neurotrophin ligand binding domain (also known a the Immunoglobulin - like domain 2). Exons 10 and 11 encode the transmembrane domain while the tyrosine kinase domain is encoded by exons 13-18.

Pseudogene

Variant transcripts exist for NTRK3, which have been termed non-catalytic (NC) as they do not contain enough sequence to mount an appropriate autophosphorylation event. These have been named NTRK3-NC1 and NTRK3 NC2.

Protein

The NTRK3 protein is composed of several regions.

Starting at the amino terminus is the signal sequence (SS) responsible for directing the newly translated protein to the cell surface.

Next is the Extracellular Ligand Binding Domain (ECD-LB), which binds Neurotrophin 3 and subsequent homo-dimerization with autophosphorylation of key tyrosine residues.

The transmembrane domain (TM) spans the plasma membrane.

The intracellular portion is composed of the protein tyrosine kinase domain (PTK) which has both the key tyrosines for autophosphorylation as well as tyrosines that are phosphorylated and act as activators of downstream molecules including Shc, PI3-Kinase and PLC-g.

Description

145 kDa protein, located on plasma membrane with an extra-cellular ligand binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. Ligand for NTRK3 is Neurotrophin 3; after binding to NTRK3, it causes dimerization and autophosphorylation of specific tyrosine phosphates, which in turn act as anchors and activators of downstream molecules such as Shc, PI3-K and PLC-g.

Expression

Primarily in central nervous system tissue with specific emphasis in hippocampus, cerebral cortex, and the granular cell layer of the cerebellum. In addition, there is a minor amount expressed in a variety of other tissues.

CFS and cellular CMN are pediatric tumors of spindle cell origin (mesoblastic origin). CFS primarily presents at birth up to 2 years of age, usually affecting the extremities. Cellular CMN, on the other hand is a pediatric spindle cell tumor of the kidney.

Prognosis

The presence of the ETV6-NTRK3 gene fusion in both CFS and cellular CMN indicate an excellent prognosis when compared to their histologically similar and more aggressive counterparts.

Cytogenetics

The ETV6-NTRK3 gene fusion is the result of a t(12;15)(p13;q25).

The amino terminus is composed of the first 5 exons from ETV6, which carries the Helix-Loop-Helix Domain (HLH) responsible for dimerization. The remainder of the protein is composed of the Protein Tyrosine Kinase domain from NTRK3. The arrow represents the point at which the ETV6 contribution ends and the NTRK3 contribution begins.

Hybrid/Mutated Gene

ETV6-NTRK3

Oncogenesis

Current speculation regarding the oncogenic mechanism of the fusion protein is related to its putative activation of the MAP Kinase pathway with resultant activation of various downstream proteins such as transcription factors. Native NTRK3 requires extracellular ligand binding of Neurotrophin 3 prior to its dimerization and autophosphorylation. ETV-6-NTRK3, however, bypasses this requirement as it contains the HLH domain from ETV6 which allows the molecule to dimerize in the absence of Neurotrophin 3 and thus remain in a constitutively activated (phosphorylated) state. Once again, the presence of ETV6-NTRK3 seems to make these particular neoplasms behave more indolent than their aggressive Ductal Carinoma counterparts, which do not harbor the ETV6-NTRK3 gene fusion.

Virtually all cases of CFS and cellular CMN to date have been associated with the ETV6-NTRK3 gene fusion. In addition these malignancies almost always have an additional copy of chromosome 11. This additional copy of chromosome 11 is not found in secretory breast carcinoma. Finally, the ETV6-NTRK3 gene fusion was found in secretory breast carcinomas of all ages (the youngest case being a 6 year old female).

Disease

Secretory Breast Carcinoma is an epithelially derived breast cancer, as opposed to the mesoblastic CFS and cellular CMN above. It can occur in the pediatric population and much more commonly in adults.

Cytogenetics

The ETV6-NTRK3 gene fusion is the result of a t(12;15)(p13;q25).

Hybrid/Mutated Gene

ETV6-NTRK3 Please see above diagrams and explanations for the protein and proposed oncogenic mechanism.